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Critical Care Egi

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RESEARCH Open Access
Association of body temperature and antipyretic
treatments with mortality of critically ill patients
with and without sepsis: multi-centered
prospective observational study
for Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group, Byung Ho Lee
1
, Daisuke Inui
2
,
Gee Young Suh
3
, Jae Yeol Kim
4
, Jae Young Kwon
5
, Jisook Park
6
, Keiichi Tada
7
, Keiji Tanaka
8
, Kenichi Ietsugu
9
,
Kenji Uehara
7
, Kentaro Dote
10
, Kimitaka Tajimi
11
, Kiyoshi Morita
12
, Koichi Matsuo
13
, Koji Hoshino
14
,
Koji Hosokawa
15
, Kook Hyun Lee
16
, Kyoung Min Lee
17
, Makoto Takatori
7
, Masaji Nishimura
2
, Masamitsu Sanui
18
,
Masanori Ito
9
, Moritoki Egi
12*
, Naofumi Honda
14
, Naoko Okayama
19
, Nobuaki Shime
15
, Ryosuke Tsuruta
20
,
Satoshi Nogami
7
, Seok-Hwa Yoon
21
, Shigeki Fujitani
22
, Shin Ok Koh
23
, Shinhiro Takeda
8
, Shinsuke Saito
9
,
Sung Jin Hong
24
, Takeshi Yamamoto
8
, Takeshi Yokoyama
14
, Takuhiro Yamaguchi
25
, Tomoki Nishiyama
26
,
Toshiko Igarashi
11
, Yasuyuki Kakihana
19
and Younsuck Koh
27
Abstract
Introduction: Fever is frequently observed in critically ill patients. An independent association of fever with
increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The
association of fever and antipyretics with mortality, however, may be different between infective and non-infective
illness.
Methods: We designed a prospective observational study to investigate the independent association of fever and
the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425
consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in
25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days
after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the
association of maximum body temperature during ICU stay (MAX
ICU
) and the use of antipyretic treatments with 28-
day mortality.
Results: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients
(51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen
independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028,
acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15,
acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group.
Relative to the reference range (MAX
ICU
36.5C to 37.4C), MAX
ICU
39.5C increased risk of 28-day mortality in
septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P =
0.11).
Conclusions: In non-septic patients, high fever ( 39.5C) independently associated with mortality, without
association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients,
* Correspondence: moriori@tg8.so-net.ne.jp
12
Department of Intensive Care, Okayama University Hospital, Okayama,
Japan
Full list of author information is available at the end of the article
et al
.
2012, 16:R33
2012 FACE study group et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of
fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or
both implications for patients with and without sepsis.
Trial registration: ClinicalTrials.gov: NCT00940654
Keywords: body temperature, antipyretic, fever, critical illness, mortality
Introduction
Fever frequently occurs in critically ill patients [1].
Although fever is primarily a symptom of infection [2],
it also occurs as a hosts response to non-infectious
inflammatory stimulus [3]. Currently, the effect of anti-
pyretics on patient outcomes remains unclear and there
are no recommendations for antipyretic treatments for
non-neurological critically ill patients [2,4].
Fever may have detrimental effects, especially in life-
threatening illnesses, by increasing the metabolic rate,
minute ventilation and oxygen consumption, and by
adversely affecting neurological outcomes [5-7]. Thus,
antipyretic treatments are frequently administered in
critically ill patients both with and without infectious
diseases [8-10].
Fever below a fatal temperature, however, could be a
host response against infectious disease resulting in
reduced bacterial growth, promotion of the synthesis of
antibodies and cytokines, and activation of T cells, neu-
trophils and macrophages [11-13]. Several studies have
suggested that suppression of infective febrile responses
with antipyretic treatments might worsen outcomes
[14,15].
Based on the studies mentioned above, it would be
desirable to understand whether there is an independent
association of fever and the use of antipyretic treatments
with mortality in infective critical ill patients and
whether this association is the same in non-infective cri-
tical ill patients.
Accordingly, we conducted a multicenter prospective
observational study to test the hypothesis that an inde-
pendent association of fever and antipyretic treatments
with mortality was significantly modified by the pre-
sence of sepsis at admission to the ICU.
Materials and methods
Study design
This study was a prospective observational investigation
conducted in 25 hospitals: 10 in Korea and 15 in Japan.
Among these 25 hospitals, 20 were academic tertiary
care hospitals and 5 were community hospitals. Partici-
pating hospitals range in size from 248 to 2,860 beds
(median of 736) and included a total of 1,002 ICU beds
(median of 20 beds per ICU). Data collection and data
analysis for this study were approved by each of the
local institutional ethics committees, and each waived
the requirement for informed consent.
Patients
At each participating site, all adult patients who
required intensive care for more than 48 hours from 1
September 2009 to 30 November 2009 were candidates
for enrollment in the study; we excluded patients with
post-cardiac arrest, post craniotomy, traumatic brain
injury, central nervous system infection, subarachnoid
hemorrhage, intracerebral hemorrhage or stroke at their
ICU admission.
We separated our cohorts into patients with and with-
out sepsis for the first 24 hours of ICU admission. Sep-
sis was defined as the presence of microbiologically
proven, clinically affirmed or suspected infection along
with the presence of systemic inflammatory response
syndrome [16,17].
Data collection
Demographic data
Age, sex, reason for admission, use of mechanical venti-
lation and Acute Physiology and Chronic Health Evalua-
tion (APACHE) II score [18] were recorded. Coding for
major admission diagnosis was categorized as cardiac or
vascular disease, thoracic or respiratory disease, renal or
metabolic disease, gastrointestinal tract disease, and
other.
Body temperature
We recorded four-hourly body temperature until either
time of ICU discharge or 28 days after ICU admission,
whichever occurred first. Measuring methods included
use of pulmonary artery and bladder catheter thermis-
tors, tympanic membrane and axillary thermometers.
When body temperature was simultaneously measured
using more than one method, we recorded the value
measured by the method most preferred by the Ameri-
can College of Critical Care Medicine and the Infectious
Diseases Society of America [2].
Information for antipyretic treatments
While no standardized protocols for the prevention or
treatment of fever were applied across the participating
ICUs, we recorded all the antipyretic treatments during
ICU stay; including non-steroidal anti-inflammatory
drugs (NSAIDs), acetaminophen and physical cooling.
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2012, 16:R33
Body temperature at commencement of antipyretic
treatment was also recorded. Information for NSAIDs
and acetaminophen was recorded only when these were
administered for fever management, not for pain con-
trol. Physical cooling methods included external air and
water blanket techniques, and internal cold gastric
lavage or cold fluid infusion.
Outcome
The primary outcome of interest was mortality up to 28
days after ICU admission, and the association of this
with peak body temperature during ICU stay and admi-
nistered antipyretic treatments. Patients who were dis-
charged alive from the hospital before Day 28 were
defined as survived.
Statistical analysis
Categorical variables were summarized using propor-
tions and compared between groups using the chi-
square test and continuous variables were summarized
using mean (SD) or median (interquartile range; IQR)
and compared between groups using Students t-test or
the Wilcoxon rank-sum test as appropriate.
To determine the severity of fever, we considered
maximum body temperature (MAX
ICU
), the highest
body temperature recorded during ICU stay. As the
relationship between body temperature and mortality
may not be linear, we treated body temperature as a
categorical variable. MAX
ICU
was analyzed in five range
categories: (A) < 36.5C, (B) 36.5C to 37.4C, (C) 37.5C
to 38.4C, (D) 38.5C to 39.4C and (E) 39.5C. Odds
ratios are reported relative to a reference body tempera-
ture, defined here as category (B) (36.5C to 37.4C).
Additionally, we performed survival log-rank test to
compare each range categories.
We performed multivariate logistic regression analysis,
treating as independent variables, site, age, use of
mechanical ventilation, APACHE-II score with the body
temperature component removed [18], category of ICU
admission, whether surgical or medical admission, sub-
group of MAX
ICU
, application of antipyretic treatment;
the dependent variable was death within 28 days of
admission. Model calibration was determined using the
Hosmer-Lemeshow test for goodness of fit. Results from
the multivariate models are reported using odds ratios
with 95% confidence intervals.
For sensitivity analysis, we further developed another
multivariate model among patients with lowest body
temperature during ICU stay > 35C. We defined this
threshold (> 35C) as a recent large epidemiological
study defined 35C as the threshold of moderate to
severe hypothermia [19].
We assumed 50% of the study patients had sepsis, a
quarter of them were prescribed antipyretic therapy and
the mortality of ICU patients was 12%. Assuming an 8%
change in ICU mortality with antipyretic both in septic
and non-septic patients, a power of 0.80, and an a level
of 0.05, we required 1,400 participants. As we expected
to include approximately 500 participants per month,
we planned to conduct the current study for three
months.
P-values of less than 0.05 were considered statistically
significant. All analyses were performed using commer-
cially available statistical software (SPSS 19.0, SPSS Inc,
Chicago, IL, USA). Data are reported in accordance with
the guidelines laid out in Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) [20].
Results
We studied 1,429 consecutive patients. We excluded
four patients for whom data were incomplete (4/1,429,
0.3%), leaving a total of 1,425 patients with 63,441 body
temperature measurements eligible for inclusion in the
study. Seventy-two percent of body temperature was
measured by axillary thermometers, 16% by bladder
catheter thermistors, 9% by tympanic membrane ther-
mometers and 3% by pulmonary artery catheter thermis-
tors. The median APACHE II score was 17, and 28-day
mortality was 12.0%. The median length of stay in ICU
was 7 days and in hospital 26 days. Among the 1,425
patients, 606 patients met the criteria for sepsis during
the first 24 h. The remaining 819 patients were without
sepsis (Figure 1).
Table 1 provides clinical characteristics, MAX
ICU
and
antipyretic treatments for septic and non-septic patients
and for the total cohort. Septic patients tended to be
more severely ill, older and were less likely to be post-
operative patients or to have required mechanical venti-
lation during ICU stay. The 28-day mortality in septic
patients was significantly higher than in non-septic
patients.
Septic patients exhibited significantly higher MAX
ICU
than non-septic patients (38.3C vs. 37.8C, P < 0.001).
MAX
ICU
in septic patients was more frequently in the
higher range ( 38.5C) (Table 1). This difference was
present for the first seven days of ICU stay (Figure 2).
Table 2 shows 28-day mortality and odds ratio for
each range of MAX
ICU
relative to the reference range of
36.5C to 37.4C in septic and non-septic patients,
respectively. Mortality did not relate to MAX
ICU
in sep-
tic patients. By contrast, for non-septic patients, 28-day
mortality increased according to MAX
ICU
, and was sig-
nificantly greater when MAX
ICU
was 38.5C (odds
ratio; 5.13 (P < 0.007) and 13.4 (P < 0.001), 38.5C to
39.4C and 39.5C, respectively). There was no signifi-
cant difference in 28-day mortality between patients
with single and multiple episodes of MAX
ICU
39.5C.
Mortality for septic patients with MAX
ICU
< 36.5C was
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as high as 50%, but no significant difference was
detected owing to the small number of patients in this
category (n = 4) (odds 3.08, P = 0.57).
Figure 3 shows Kaplan-Meier estimates for the prob-
ability, which at 28 days was greater in non-septic
patients with MAX
ICU
38.5C than those with tem-
peratures of 36.5C to 37.4C. In septic patients, there
were no significant differences of provability of survival
in each category compared with patients of MAX
ICU
with 36.5C to 37.4C.
Antipyretic treatment was applied 4,863 times to 737
patients (51.7%). NSAIDs were administered 429 times
to 130 patients (9.1%), acetaminophen was administered
571 times to 148 patients (10.4%) and physical cooling
was applied 3,863 times to 671 patients (47.1%). Delta
body temperature from application of antipyretic to next
temperature monitoring was -0.3C (IQR; -0.7, 0.0) and
-0.4C (IQR; -0.9, -0.2), for NSAIDs and acetaminophen
respectively, which is significantly greater than -0.1C
for physical cooling (P < 0.001) (Table 1).
Figure 3 shows the proportion of patients who
received pharmacological antipyretic treatments
(NSAIDs, acetaminophen or both) in each subgroup.
For the subgroup with MAX
ICU
of 37.5C to 38.4C, the
proportion of patients who received pharmacological
antipyretic treatments was significantly higher than in
non-septic patients (P = 0.007). For the rest of the sub-
groups, it was not significantly different between
patients with and without sepsis (38.5C to 39.4C, P =
0.62; 39.5C, P = 0.25). Acetaminophen was used
more frequently for septic patients, and NSAIDs for
non-septic patients in each range of MAX
ICU
(P <
0.001) (Figure 3). Figure 4 shows the proportion of sep-
tic and non-septic patients who received physical cool-
ing. Physical cooling was applied frequently in septic
patients, when MAX
ICU
was 39.4C (Figure 5).
Table 3 shows univariate comparisons of patient demo-
graphic data and antipyretic treatments. In septic patients,
the use of NSAIDs and acetaminophen was significantly
associated with increased mortality (odds ratio: NSAIDs
2.32, P = 0.02; acetaminophen 2.30, P = 0.002) (Table 3).
By contrast, for non-septic patients, the pharmacological
antipyretic treatments were not associated with mortality
(odds ratio: NSAIDs 0.20, P = 0.08; acetaminophen 0.69, P
= 0.72). Physical cooling was associated with mortality in
neither septic nor non-septic patients (odds ratio: with
sepsis 1.00, P = 0.99; without sepsis 1.14, P = 0.74).
Multivariate analysis
As shown in Table 3, the presence of confounders, such
as severity of illness, age, reason for ICU admission and
mechanical ventilation requirement, necessitated
1429 critically ill patients
without any neurological injury and derangement
1425 patients were eligible for study
4 patients were excluded
(body temperature was not adequately collected)
606 patients with sepsis
at admission of ICU
819 patients without sepsis
at admission of ICU
Figure 1 Flow chart showing current study. ICU, intensive care units.
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2012, 16:R33
multivariate analysis adjusting for relevant predictors of
28-day mortality.
In septic patients relative to the reference range (36.5
C to 37.4C), MAX
ICU
37.5C to 38.4C was associated
with decreased mortality (adjusted odds ratio 0.45, P =
0.014) and MAX
ICU
38.5C was not (adjusted odds
ratio 38.5C to 39.4C; 0.52, P = 0.09, 39.5C; 0.47, P =
0.11). In non-septic patients, adjusted risk of death was
increased as MAX
ICU
increased, and MAX
ICU
39.5C
was associated with mortality (adjusted odds ratio 8.14,
P = 0.01) (Table 4).
In septic patients, administration of NSAIDs or acetami-
nophen was independently associated with mortality
(adjusted odds ratio: NSAIDs 2.61, P = 0.028; acetamino-
phen 2.05, P = 0.01). In non-septic patients, the pharmaco-
logical antipyretic treatments were not associated with
mortality (adjusted odds ratio: NSAIDs 0.22, P = 0.15;
acetaminophen 0.58, P = 0.63) (Table 4). The model was a
good fit for data from both groups (Hosmer-Lemeshow:
with sepsis, P = 0.21, without sepsis, P = 0.89).
To exclude the possible effects of hypothermia, we
further performed multivariate logistic analysis exclud-
ing data from 106 patients with low body temperature
( 35C) during ICU stay (Table 5). Even in this model,
administration of NSAIDs and acetaminophen in septic
patients was independently associated with mortality
(adjusted odds ratio: NSAIDs 2.48, P = 0.04; acetamino-
phen 1.95, P = 0.03). Meanwhile, for non-septic patients,
MAX
ICU
38.5C was associated with mortality
(adjusted odds ratio 38.5C to 39.4C; 7.49, P = 0.02,
39.5C; 11.7, P = 0.02).
Discussion
Key results
We performed a study to explore the relationship of
fever and antipyretic treatments with 28-day mortality
Table 1 Comparison of baseline characteristics of patients with and without sepsis
Patients
with sepsis
(N = 606)
Patients
without sepsis
(N = 819)
P-value Total cohort
(N = 1425)
28-day mortality n (%) 135 (22.3%) 36 (4.4%) < 0.001 171 (12.0%)
Gender (male) n (%) 385 (63.5%) 508 (62%) 0.56 893 (62.7%)
Age (y.o, IQR) 67 (55, 75) 65 (54, 73) 0.015 66 (54, 74)
APACHE II score (IQR) 21 (16, 25) 14 (10, 18) < 0.001 17 (12, 22)
Mechanical ventilation requirement n (%) 429 (70.8%) 528 (64.5%) 0.01 957 (67.2%)
Postoperative admission n (%) 68 (11.2%) 538 (65.7%) < 0.001 602 (42.2%)
Reasons for admission n (%)
Cardiac or vascular disease 109 (18.0%) 435 (53.1%) < 0.001 544 (38.2%)
Thoracic or respiratory disease 343 (56.6%) 205 (25.0%) < 0.001 548 (38.4%)
Renal or metabolic disease 61 (10.0%) 54 (6.6%) 0.018 115 (8.1%)
Gastrointestinal tract disease 68 (11.2%) 108 (13.1%) 0.26 176 (12.4%)
Other 25 (4.1%) 17 (2.1%) 0.024 42 (2.9%)
Length of stay in ICU 8 (5, 14) 5 (4, 7) < 0.001 6 (4, 10)
MAX
ICU
(C, IQR) 38.3 (37.7, 39.0) 37.8 (37.4, 38.3) < 0.001 38.0 (37.5, 38.6)
< 36.5C 4 (0.7%) 2 (0.2%) 0.43 6 (0.4%)
36.5C to 37.4C 98 (16.2%) 240 (29.3%) < 0.001 338 (23.7%)
37.5C to 38.4C 237 (39.1%) 425 (52.0%) < 0.001 662 (46.5%)
38.5C to 39.4C 185 (30.5%) 125 (15.3%) < 0.001 310 (21.8%)
39.5C 82 (13.5%) 27 (3.3%) < 0.001 109 (7.6%)
NSAIDs
Number of patients administered n (%) 31 (5.1%) 99 (12.1%) < 0.001 130 (9.1%)
Delta body temperature* (C, IQR) -0.3 (-0.8, 0.0) -0.4 (-0.7, 0.0) 0.57 -0.3 (-0.7, 0.0)
Acetaminophen
Number of patients administered n (%) 116 (19.1%) 32 (3.9%) < 0.001 148 (10.4%)
Delta body temperature* (C, IQR) -0.4 (-0.8, -0.2) -0.3 (-0.7, 0.0) 0.14 -0.4 (-0.9, -0.2)
Physical cooling
Number of patients administered n (%) 307 (50.7%) 364 (44.4%) 0.02 671 (47.1%)
Delta body temperature* (C, IQR) -0.2 (-0.5, 0.0) -0.1 (-0.3, 0.0) < 0.001 -0.1 (-0.3, 0.0)
APACHE, Acute Physiology and Chronic Health Evaluation; IQR, 25%, 75% interquartile; MAX
ICU
, maximum body temperature during ICU stay; NSAIDs, non-steroid
anti-inflammatory drugs
*, Delta body temperature from application of antipyretic to next temperature monitoring
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37.0
37.2
37.4
37.6
37.8
38.0
Septic patients
Non-septic patients
(Error bar; 95%CI)
(P<0.05)
D
a
i
l
y

p
e
a
k

b
o
d
y

t
e
m
p
e
r
a
t
u
r
e

(
e

(
C
)

Day after ICU admission (day)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Figure 2 Mean peak daily temperature of patients with and without sepsis. The white circles indicate the mean peak daily temperature in
patients with sepsis. The black circles indicate the mean peak daily temperature in patients without sepsis. For the first seven days after
admission, peak body temperature of patients with sepsis was significantly higher than of patients without sepsis. CI, confidential interval; ICU,
intensive care unit.
Table 2 Maximum body temperature during ICU stay and 28-day mortality of patients with and without sepsis.
MAX
ICU
Patients with sepsis
(N = 606)
Patients without sepsis
(N = 819)
28-day
mortality
Unadjusted
odds ratio (95% CI)
28-day
mortality
Unadjusted
odds ratio (95% CI)
< 36.5C 2/4
(50.0%)
3.08 (0.41, 23.1)
(P = 0.57)
0/2
(0%)
n.a.
36.5C to 37.4C 24/98
(24.5%)
1
(reference)
4/240
(1.7%)
1
(reference)
37.5C to 38.4C 40/237
(16.9%)
0.63 (0.35, 1.11)
(P = 0.14)
17/425
(4.0%)
2.46 (0.82, 7.40)
(P = 0.44)
38.5C to 39.4C 44/185
(23.8%)
0.96 (0.54, 1.70)
(P = 0.99)
10/125
(8.0%)
5.13 (1.58, 16.7)
(P = 0.007)
39.5C 25/82
(30.5%)
1.35 (0.70, 2.61)
(P = 0.46)
5/27
(18.5%)
13.4 (3.35, 53.6)
(P < 0.001)
Unadjusted odds ratio was reported relative to a reference body temperature defined as category 36.5C to 37.4C.
CI, confidential interval; ICU, intensive care unit; MAX
ICU
, maximum body temperature during an ICU stay; n.a., not applicable (no patients in this category)
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in critically ill patients and to quantify the difference of
its association between patients with and without sepsis.
We found that in septic patients, compared with the
36.5C to 37.4C subgroup, MAX
ICU
37.5C to 38.4C
was associated with decreased mortality and MAX
ICU

38.5C was not independently associated with mortality.
By contrast, in non-septic patients, high fever ( 39.5C)
was independently associated with mortality. We also
found significant interactions between mortality and
treatment with NSAIDs or acetaminophen only in septic
patients.
Limitations of this study
Our study had several limitations. First, because it was
designed as an observational study without standardized
protocols for antipyretic treatments, the findings can
only show association and not causality. Thus, our
results can only be viewed as useful for generating
hypotheses.
The methods of body temperature monitoring were
not standardized. Furthermore, the majority of the body
temperatures was measured by axillary thermometers,
although core temperature is less influenced by external
factors and more accurately reflects temperature of the
vital organs [21]. Additionally, it is possible that the
sickest patients were more likely to have had invasive
measurements of core temperature, resulting in rela-
tively higher values. The proportion of methods of body
temperature monitoring, however, used in septic
patients was not significantly different from non-septic
patients. Thus, any bias-related body temperature moni-
toring would similarly influence both cohorts. Nonethe-
less, our finding may be accentuated due to changes in
circulation occurring during the progression of sepsis
environmental temperature [22]. In this regard, our
finding should be confirmed or refuted by further stu-
dies using core body temperature monitoring.
Although the proportion of patients treated with phar-
macological antipyretic treatments were similar in both
septic and non-septic patients, NSAIDs were more fre-
quently administered to non-septic patients, while aceta-
minophen was used more frequently for septic patients.
Additionally, acetaminophen was less frequently admi-
nistered in the present study than in other studies.
Young et al. reported that acetaminophen was adminis-
tered to 58% to 70% of septic patients [10], while only
to about 20% in our patients. Physical cooling was
applied more frequently in our population than reported
elsewhere [10]. These facts may influence their associa-
tion with mortality. Thus, we duly note that our findings
may not be applicable to other settings where antipyre-
tic procedures are different. Additionally, we studied in
only two countries and our findings may not be general-
izable to other countries, especially those with different
medical systems.
We used delta body temperature after antipyretic
treatments to compare the strength of each antipyretic
effect. We should note that this index did not reflect the
absolute reduction of body temperature after antipyretic
procedures, as the timing of temperature measurement
Day from admission
0 4 8 12 16 20 24 28
S
u
r
v
i
v
a
l
0.0
0.7
0.8
0.9
1.0
36.5-37.4
o
C
37.5-38.4
o
C
38.5-39.4
o
C
39.5
o
C
Day from admission
0 4 8 12 16 20 24 28
S
u
r
v
i
v
a
l
0.0
0.7
0.8
0.9
1.0
36.5-37.4
o
C
37.5-38.4
o
C
38.5-39.4
o
C
39.5
o
C
*
*
Septic patients
Non-septic patients
Figure 3 Maximum body temperature during ICU stay and survival of patients with and without sepsis. This figure shows Kaplan-Meier
estimates for the probability of survival, which at 28 days was greater in non-septic patients with MAX
ICU
38.5C to 39.4C and 39.5C than
those with 36.5C to 37.4C. In septic patients, there were no significant differences of provability of survival in each category compared with
patients of MAX
ICU
with 36.5C to 37.4C. *, significantly different probability of survival at 28 days after ICU admission than patients with 36.5C
to 37.4C.
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after antipyretics was not standardized and there might
not be a linear relationship between individual antipyre-
tic treatment and the next body temperature.
Finally, we excluded critically ill patients with neurologi-
cal injury. It is widely accepted that fever adversely affects
the outcome of critically ill patients with neurological injury
[23,24] and should be treated [6,7]. By contrast, there is no
clear recommendation for antipyretic treatments for non-
neurological critically ill patients [2,4,25]. Thus, we chose to
exclude patients with neurological injury.
Interpretation
Although we reported associations and cannot assume
causality, our finding was consistent with previous
studies [26,27], suggesting that fever could be a host
response that protects against infectious diseases [11-13]
and use of antipyretic treatments to suppress the febrile
response to infection might worsen outcomes [14,15].
The association of fever with mortality varied accord-
ing to the level of fever and it was independently asso-
ciated with mortality only in subgroup 39.5C of
patients without sepsis. We assume that high fever seen
in patients without sepsis was likely caused by infection
subsequent to ICU admission and this may account for
the higher mortality. We did find, however, that the
association of MAX
ICU
and mortality were similar in
patients with no sign of infection during ICU stay
(Additional file 1).
0
10
20
30
40
50
60
37.5-38.4 38.5-39.4 39.5 37.5-38.4 38.5-39.4 39.5 MAX
ICU
(
o
C)
Septic patients Non-septic patients
NSAIDs
NSAIDs & Acetaminophen
Acetaminophen
(%)
Figure 4 Administration of pharmacological antipyretic treatments (NSAIDs and/or acetaminophen) in each MAX
ICU
category. Data
show patients categorized in subgroups according to MAX
ICU
value range: 37.5C to 38.4C, 38.5C to 39.4C and 39.5C. White bar, patients
given NSAIDs; black bar, patients given acetaminophen; gray bar, patients given both NSAIDs and acetaminophen. For the subgroup with
MAX
ICU
of 37.5C to 38.4C, the proportion of patients received pharmacological antipyretic treatments was significantly higher in non-septic
patients (P = 0.007). For the rest of the subgroups, it was not significantly different between patients with and without sepsis (38.5C to 39.4C, P
= 0.62; 39.5C, P = 0.25). Acetaminophen was used more frequently for patients with sepsis, and NSAIDs for patients without sepsis in each
MAX
CAT
subgroup (P < 0.001). MAX
ICU
, maximum body temperature recorded during ICU stay; NSAIDs: non-steroid anti-inflammatory drugs.
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A large epidemiological study has revealed that the
presence of fever ( 38.3C) is not associated with
increased ICU mortality (13% vs. 12%: P = 0.08), but
that high fever ( 39.5C) was associated with signifi-
cantly increased mortality (20.3% vs. 12%, P < 0.001) [1].
High fever can result in cardiac arrhythmias, tachycar-
dia, increased oxygen demand, convulsions and brain
damage [5-7]. Patients with non-infective febrile
responses may experience these deleterious effects with-
out the potential benefit of fever-related protection
against viruses or bacteria or both.
We found that the association with mortality of the
administration of NSAIDs or acetaminophen or both
was significantly different for non-septic patients than
for septic patients. There are at least four possible expla-
nations for our findings related to septic patients. First,
the infective febrile response may be effective and lower-
ing body temperature with antipyretics might be
undesirable for septic patients. Fever is thought to inhi-
bit the activity of viruses and bacteria [11-13] and anti-
pyretic treatments shown to worsen outcomes in
various animal and human studies [14,15]. The apparent
antipyretic effects of NSAIDs and acetaminophen com-
pared with physical cooling seen in our study lends
weight to this hypothesis.
Second, in septic patients, administration of NSAIDs
and acetaminophen may be toxic, as they might be asso-
ciated with hypotension and renal dysfunction [28,29].
We could not assess this hypothesis in the current
study.
Third, mortality is higher for septic patients who fail
to develop a fever. We found the unadjusted mortality
was as high as 66% in patients with MAX
ICU
< 36.5C.
This finding may also support the argument that fever is
naturally protective. For sensitive analysis to avoid the
bias of hypothermia (defined as lowest body temperature
0
20
40
60
80
100
37.5-38.4 38.5-39.4 39.5 37.5-38.4 38.5-39.4 39.5 MAX
ICU
(
o
C)
Patients with sepsis Patients without sepsis
*
*
(%)
Figure 5 Use of physical cooling in each MAX
ICU
category of patients with and without sepsis. Data show patients categorized in
subgroups according to MAX
ICU
value range: 37.5C to 38.4C, 38.5C to 39.4C, and 39.5C. *statistically significant difference between patients
with and without sepsis. MAX
ICU
, maximum body temperature recorded during ICU stay.
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Table 3 Comparison of baseline characteristics and antipyretic treatments of survivors and non-survivors
Patients with sepsis Patients without sepsis
Survivors
(N = 471)
Non-survivors
(N = 135)
P-value Survivors
(N = 783)
Non-survivors
(N = 36)
P-value
Gender (male) n (%) 291 (61.8%) 94 (69.6%) 0.10 485 (61.9%) 23 (63.9%) 0.81
Age (y.o., IQR) 67 (54, 75) 69 (58, 78) 0.08 64 (54, 73) 74.5 (59, 81.5) 0.003
APACHE (IQR) 20 (16, 24) 24 (21, 28) < 0.001 13 (10, 18) 24 (19.5, 28) < 0.001
Postoperative admission n (%) 59 (12.5%) 9 (6.7%) 0.057 523 (66.8%) 11 (30.6%) < 0.001
Mechanical ventilation requirement n (%) 317 (67.3%) 112 (83.0%) < 0.001 498 (63.6%) 30 (83.3%) 0.016
Reasons for admission n (%)
Cardiac or vascular diseases 93 (19.7%) 16 (11.9%) 0.04 422 (53.9%) 13 (36.1%) 0.04
Thoracic or respiratory diseases 253 (53.7%) 90 (66.7%) 0.007 193 (24.6%) 12 (33.3%) 0.24
Renal or metabolic disease 48 (10.2%) 13 (9.6%) 0.85 51 (6.5%) 3 (8.3%) 0.67
Gastrointestinal tract diseases 56 (11.9%) 12 (8.9%) 0.33 102 (13%) 6 (16.7%) 0.53
Other 21 (4.5%) 4 (3%) 0.44 15 (1.9%) 2 (5.6%) 0.13
Length of stay in ICU 8 (5, 14) 9 (5, 15) 0.74 5 (4, 7) 5 (4, 9) 0.11
NSAIDs
Number of patients n (%)
(Un adjusted odds ratio (95% CI))
19 (4%) 12 (8.9%) 0.02 98 (12.5%) 1 (2.8%) 0.08
(2.32 (1.10, 4.91)) (0.20 (0.03, 1.47))
Delta body temperature* (C, IQR) -0.4 (-0.9, -0.1) -0.1 (-0.6, 0.0) 0.08 -0.4 (-0.7, 0) 0.0 (0.0, 0.0) 0.30
Acetaminophen n (%)
Number of patients n (%)
(Un adjusted odds ratio (95%CI))
75 (15.9%) 41 (30.4%) 0.002 31 (4%) 1 (2.8%) 0.72
(2.30 (1.48, 3.58)) (0.69 (0.09, 5.23))
Delta body temperature* (C, IQR) -0.4 (-1.1, -0.1) -0.4 (-0.9, -0.2) 0.94 -0.3 (-0.7, 0.0) -0.9 (-0.9, -0.9) 0.28
Cooling n (%)
Number of patients n (%)
(Unadjusted odds ratio (95%CI))
223 (47.3%) 64 (47.4%) 0.99 366 (46.7%) 18 (50%) 0.74
(1.00 (0.68, 1.46)) (1.14 (0.58, 2.22))
Delta body temperature* (C, IQR) -0.2 (-0.4, 0) -0.2 (-0.5, 0) 0.55 -0.1 (-0.3, 0) -0.1 (-0.4, 0) 0.16
APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidential interval; IQR, 25%, 75% interquartile; NSAIDs, non-steroid anti-inflammatory drugs
*, Delta body temperature from application of antipyretic to next temperature monitoring
Table 4 Multivariate logistic analysis for 28-day mortality
Patients with sepsis
(N = 606)
Patients without sepsis
(N = 819)
Adjusted odds ratio
(95% CI)
P-value Adjusted odds ratio
(95% CI)
P-value
Age (y.o., IQR) 1.01 (0.99, 1.02) 0.32 1.01 (0.98, 1.04) 0.39
APACHE (IQR) 1.09 (1.05, 1.12) < 0.001 1.19 (1.12, 1.27) < 0.001
Postoperative admission n (%) 0.81 (0.36, 1.85) 0.62 0.56 (0.24, 1.29) 0.17
Mechanical ventilation requirement n (%) 1.72 (1.01, 2.94) 0.045 3.85 (1.40, 10.6) 0.01
Cardiac or vascular diseases 0.87 (0.43, 1.76) 0.70 1.03 (0.38, 2.75) 0.96
Thoracic or respiratory diseases 1.71 (0.99, 2.94) 0.053 1.87 (0.70, 4.97) 0.21
Max. body temp. during ICU stay
37.5C to 38.4C (vs. 36.5C to 37.4C) 0.45 (0.24, 0.85) 0.014 1.61 (0.56, 4.68) 0.38
38.5C to 39.4C (vs. 36.5C to 37.4C) 0.52 (0.24, 1.1) 0.09 3.34 (0.88, 12.69) 0.08
39.5C (vs. 36.5C -37.4C) 0.47 (0.19, 1.18) 0.11 8.14 (1.67, 39.59) 0.01
NSAIDs 2.61 (1.11, 6.11) 0.028 0.22 (0.03, 1.74) 0.15
Acetaminophen 2.05 (1.19, 3.55) 0.01 0.58 (0.06, 5.26) 0.63
Cooling 1.2 (0.70, 2.05) 0.50 0.71 (0.30, 1.69) 0.44
APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidential interval; MAX
ICU
, maximum body temperature during an ICU stay; NSAIDs, non-steroidal
anti-inflammatory drugs
Subgroup with MAX
ICU
< 36.5C was excluded from this analysis because only three patients with sepsis and none without fell within this temperature range.
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< 35.0C.), we performed further multivariate analysis
and found a similar association of the use of pharmaco-
logical antipyretic with mortality. Fourth, any combina-
tion of the above factors might also apply.
There is limited information on the effect of antipyre-
tics on patient outcomes and there are no recommenda-
tions for antipyretic treatments for febrile patients with
or without infectious diseases [2,4]. One study of trauma
patients was abandoned early with the 82
nd
patient on
instruction of a safety monitoring board. This study
reported the trend toward increased risk of infection
and death in patients when acetaminophen and physical
cooling were aggressively used [30]. Additionally, two
studies reported that short-term therapy with ibuprofen
in patients with sepsis did not influence mortality
[31,32]. To our knowledge, this study is the first multi-
center examination of the epidemiology and outcome
associations of antipyretic treatments [33]. While the
clinical benefits and risk of antipyretic treatments can
only be properly assessed in a randomized controlled
trial; until such time, our findings do have some practi-
cal implications.
Conclusions
In conclusion, the association with mortality of fever
and type of antipyretic treatment was different between
patients with and without sepsis at admission to ICU.
For non-septic patients, MAX
ICU
39.5C was asso-
ciated with 28-day mortality. Meanwhile, for septic
patients, administration of NSAIDs and acetaminophen
was independently associated with increased mortality.
Since many ICU patients are or become febrile and
antipyretic treatments are common, further studies now
appear desirable to confirm or refute our observations.
Key messages
The association of fever with mortality was differ-
ent for patients with and without sepsis at admission
to ICU.
For patients without sepsis, MAX
ICU
39.5C was
associated with 28-day mortality.
The association of pharmacological antipyretic
treatments with mortality was different for patients
with and without sepsis at admission of ICU.
For patients without sepsis, administration of
NSAIDs and acetaminophen was independently
associated with increased mortality.
Writing committee (contributions)
Korea: Younsuck Koh, M.D. PhD (Division of Pulmon-
ary and Critical Care Medicine, Department of Internal
Medicine, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, republic of Korea); Jae Yeol
Kim, M.D. (Department of Pulmonary and Critical Care
Medicine, Chung-Ang University College of Medicine,
Seoul, Republic of Korea); and Gee Young Suh, M.D.
(Division of Pulmonary and Critical Care Medicine,
Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, Republic of Korea).
Japan: Masaji Nishimura, M.D. PhD (Department of
Emergency and Critical Care Medicine, Tokushima Uni-
versity Hospital, Tokushima, Japan) and Moritoki Egi,
M.D. (Department of Intensive Care, Okayama Univer-
sity Hospital, Okayama, Japan).
Table 5 Multivariate logistic analysis for 28-day mortality in patients with lowest body temperature > 35C
Patients with sepsis
(N = 507)
Patients without sepsis
(N = 715)
Adjusted odds ratio
(95% CI)
P-value Adjusted odds ratio
(95% CI)
P-value
Age (y.o., IQR) 1.02 (1.00, 1.03) 0.08 1.01 (0.98, 1.05) 0.52
APACHE (IQR) 1.07 (1.03, 1.11) < 0.001 1.20 (1.11, 1.30) < 0.001
Postoperative admission n (%) 0.79 (0.32, 1.91) 0.59 0.57 (0.21, 1.52) 0.26
Mechanical ventilation requirement n (%) 1.76 (0.98, 3.14) 0.06 3.49 (1.14, 10.7) 0.03
Cardiac or vascular diseases 0.85 (0.39, 1.82) 0.67 0.73 (0.24, 2.21) 0.57
Thoracic or respiratory diseases 1.23 (0.66, 2.28) 0.51 1.24 (0.40, 3.78) 0.71
MAX
ICU
37.5C to 38.4C (vs. 36.5C to 37.4C) 0.42 (0.20, 0.88) 0.02 3.18 (0.78, 12.9) 0.11
38.5C to 39.4C (vs. 36.5C to 37.4C) 0.60 (0.25, 1.43) 0.25 7.49 (1.47, 38.1) 0.02
39.5C (vs. 36.5C to 37.4C) 0.59 (0.21, 1.68) 0.32 11.7 (1.58, 87.0) 0.02
NSAIDs 2.48 (1.02, 6.01) 0.04 0.26 (0.032, 2.19) 0.22
Acetaminophen 1.95 (1.06, 3.57) 0.03 0.61 (0.23, 1.61) 0.32
Cooling 1.23 (0.69, 2.21) 0.47 1.26 (0.14, 11.0) 0.84
APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidential interval; MAX
ICU
, maximum body temperature during an ICU stay; NSAIDs, non-steroid
anti-inflammatory drugs
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ME and MN conceived the study. ME, MN, YK, JYK
and GYS participated in the design of the study and
coordinated patient enrollment and data collection for
their respective countries. MN and JYK managed the
data collection website for the respective countries. ME
performed the statistical analyses. ME, MN, YK, JYK
and GYS participated in data interpretation and drafted
the manuscript. All authors read and approved the final
manuscript.
Additional material
Additional file 1: Maximum body temperature during ICU stay and
28-day mortality of patients with and without sign of infection.
Abbreviations
APACHE: Acute Physiology and Chronic Health Evaluation; ICU: intensive care
unit; MAX
ICU:
maximum body temperature during ICU stay; NSAIDs: non-
steroidal anti-inflammatory drugs; STROBE: Strengthening the Reporting of
Observational Studies in Epidemiology.
Acknowledgements
The Korean Society of Critical Care Medicine and the Japanese Society of
Intensive Care Medicine supported the travel expense for research
committee members to JAKOICS meetings.
Author details
1
Department of Anesthesiology, St. Pauls Hospital, Catholic University of
Korea, Seoul, Republic of Korea.
2
Department of Emergency and Critical Care
Medicine, Tokushima University Hospital, Tokushima, Japan.
3
Division of
Pulmonary and Critical Care Medicine, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
4
Department of Pulmonary and Critical Care Medicine, Chung-Ang University
College of Medicine, Seoul, Republic of Korea.
5
Department of
Anesthesiology and Pain Medicine, Pusan National University School of
Medicine, Busan, Republic of Korea.
6
School of Media, Seoul Womens
University, Seoul, Republic of Korea.
7
Department of Anesthesiology and
Intensive Care Medicine, Hiroshima City Hospital, Hiroshima, Japan.
8
Division
of Intensive and Coronary Care Unit, Nippon Medical School Hospital, Tokyo,
Japan.
9
Tonami General Hospital, Toyama, Japan.
10
Intensive Care Division,
Ehime University Hospital, Ehime, Japan.
11
Emergency & Critical Care
Medicine, Akita University Graduate School of Medicine, Akita, Japan.
12
Department of Intensive Care, Okayama University Hospital, Okayama,
Japan.
13
Department of Internal Medicine, Misato Kenwa Hospital, Saitama,
Japan.
14
Intensive Care Unit, Department of Anesthesiology, Teine Keijinkai
Hospital, Sapporo, Japan.
15
Department of Anesthesiology, Kyoto Prefectural
University of Medicine, Kyoto, Japan.
16
Department of Anesthesiology and
Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
17
Anesthesiology and Critical Cate Medicine, Konkuk University Hospital,
Seoul, Republic of Korea.
18
Department of Anesthesiology and Critical Care
Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
19
Division of Intensive Care Medicine, Kagoshima University Hospital,
Kagoshima, Japan.
20
Advanced Medical Emergency and Critical Care Center,
Yamaguchi University Hospital, Yamaguchi, Japan.
21
Department of
Anesthesiology and Pain Medicine, Chungnam National University Hospital,
Daejeon, Republic of Korea.
22
Department of Emergency and Critical Care
Medicine, St. Marianna University, Kanagawa, Japan.
23
Department of
Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute,
Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of
Korea.
24
Department of Anesthesiology and Pain Medicine, Incheon St
Marys Hospital, Catholic University of Korea, Medical College, Incheon,
Republic of Korea.
25
Innovation of New Biomedical Engineering Center,
Tohoku University, Sendai, Japan.
26
Department of Anesthesiology and
Critical Care, Kamagaya General Hospital, Kamagaya, Japan.
27
Division of
Pulmonary and Critical Care Medicine, Department of Internal Medicine,
Asan Medical Center, University of Ulsan College of Medicine, Seoul, republic
of Korea.
Competing interests
All principal investigators have no financial competing interests to disclose.
There are no conflicts of interest to disclose related to this investigation.
Received: 14 October 2011 Revised: 21 February 2012
Accepted: 28 February 2012 Published: 28 February 2012
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antipyretic treatments with mortality of critically ill patients with and
without sepsis: multi-centered prospective observational study. Critical
Care 2012 16:R33.
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